Arthropod repellents

ABSTRACT

This invention relates to a method of using compounds of the formula: ##STR1## wherein R 1  is hydrogen, alkyl or alkenyl; R 2  is hydrogen, alkyl, cycloalkyl or mononuclear aryl or R 1  and R 2 , taken together with the carbon atom to which they are attached, form a cycloalkyl or cycloalkoxyalkyl; R 3  is hydroxy, alkyl, alkoxycarbonyl, hydroxy lower alkyl or a radical of the formula: --C(═Y)NR 4  R 5  wherein R 4  is hydrogen, alkyl, alkenyl, R 5  is alkyl, alkenyl, alkoxyalkyl, carbalkoxy, mononuclear aryl, or R 4  and R 5  may be joined together with the nitrogen atom to which they are attached to form a 5 to 7 membered heterocyclic ring having from 1 to 3 hetero atoms; Y is O or S; X is alkyl, alkoxycarbonylalkyl or cyano; m is an integer of 0 to 2 and n and n&#39; are integers each having a value of 1 to 2 and the dotted line indicates an optional double bond anywhere in the ring, compositions containing said compounds as insect repellents and to novel compounds.

This application is a division application of U.S. Ser. No. 221,089 filed Dec. 29, 1980 now U.S. Pat. No. 4,357,471, which was a division application of U.S. Ser. No. 029,491 filed Apr. 12, 1979 now abandoned, which was a cotinuation-in-part application of U.S. Ser. No. 839,159 filed Oct. 3, 1977 now abandoned, which was a continuation-in-part application of U.S. Ser. No. 751,932 filed Dec. 17, 1976 now abandoned.

The search for insect repellents which have a combination of excellent repellency, high residual activity and essentially no toxicity is a continuing one due to recognition of the possible toxicity to animals or humans of many known insecticides. Since long lasting repellents avoid these problems with insecticides and provide essentially the same results, compounds having these effects are in great demand.

Accordingly, it is an object of this invention to provide novel methods for repelling arthropods, and also novel compounds and compositions useful in repelling arthropods including stable flys, mosquitoes, ticks and the like.

In accordance with the present invention, there are employed in the compositions for repelling arthropods an active ingredient having the following formula: ##STR2## wherein R¹ is hydrogen, alkyl, for example, lower alkyl of from 1 to 9 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like or alkenyl, for example, lower alkenyl of from 2 to 5 carbon atoms such as allyl and the like; R² is hydrogen, alkyl as defined in R¹, cycloalkyl, for example, cycloalkyl of from 4 to 6 nuclear carbon atoms such as cyclobutyl, cyclopentyl, cyclohexyl and the like; or mononuclear aryl such as phenyl and the like; or R¹ and R² taken together with the carbon atom to which they are attached may be joined to form a cycloalkyl or cycloalkoxyalkyl ring, for example, a cycloalkyl or cycloalkoxyalkyl ring of from 5 to 11 nuclear carbon atoms which ring may be saturated or unsaturated and substituted or unsubstituted and includes cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclohexylene, cycloheptylene, cyclononylene, bicyclo-(2.2.1)-heptyl (norbornyl), tertrahydropyranio and the like, wherein the substituent can be one or more alkyls, for example, lower alkyl of from 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl and the like, or hydroxy; R³ is hydrogen, alkyl, for example, lower alkyl of from 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, and the like; alkoxycarbonyl, for example, lower alkoxycarbonyl of from 2 to 6 carbon atoms wherein lower alkoxy can be methoxy, ethoxy, propoxy, butoxy, pentoxy and the like, hydroxy lower alkyl, such as hydroxyethyl and the like, or a radical of the formula: --C(═Y)NR⁴ R⁵ wherein R⁴ is hydrogen, alkyl, for example, lower alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 4 to 6 carbon atoms, alkenyl, for example, lower alkenyl of from 2 to 6 carbon atoms such as ethenyl, allyl, butenyl, pentenyl and the like and R⁵ is alkyl, for example, lower alkyl of from 1 to 5 carbon atoms, alkenyl, for example, lower alkenyl of from 2 to 5 carbon atoms, lower alkoxy alkyl, for example, lower alkoxy lower alkyl such as methoxyethyl and the like, carbalkoxy, for example, carbo lower alkoxy such as carbomethoxy, carboethoxy, carbobutoxy and the like, mononuclear aryl such as substituted or unsubstituted phenyl wherein the substituents may be lower alkyl, halo, lower alkoxy and the like or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic ring such as a 5 to 7 membered heterocyclic ring having from 1 to 3 heteroatoms selected from O, S or N including pyrrolidinyl, piperidyl, homopiperidyl and the like wherein the substituent may be lower alkyl, carbalkoxy, ethylenedioxy; Y is O or S; X is alkyl, for example, lower alkyl of from 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and the like; alkoxy, for example, lower alkoxy of from 1 to 5 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentoxy and the like or alkoxycarbonylalkyl, for example, lower alkoxycarbonyl lower alkyl such as methoxycarbonylmethyl, butoxycarbonylethyl and the like; m is an integer of from 0 to 2 and n and n' are integers having a value of from 1 to 2 wherein the dotted line indicates an optional double bond with the proviso that if there is a carbon-nitrogen double bond and n and n' are 1, then R¹ and R² taken together with the carbon atom to which they are attached is other than 5,5-dimethylcyclopentyl. When there is a carbon/nitrogen double bond in the ring, the R³ radical is absent.

The novel compounds of this invention have the following structural formula: ##STR3## wherein R¹, R², R³, X, m, n and n' are as defined above with the proviso that when the ring is saturated, X is alkoxycarbonylalkyl and m is at least 1 or R³ is either hydroxy lower alkyl or --C(═Y)NR⁴ R⁵ wherein R⁴ and R⁵ are as defined above or, if there is a carbon-nitrogen double bond and n and n' are each 1, then R¹ and R² taken together with the carbon atom to which they are attached is other than 5,5-dimethylcyclopentyl.

A preferred embodiment of this invention relates to novel compounds having the following formula: ##STR4## wherein R⁷ is hydrogen; R⁸ is lower alkyl of from 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, and the like or lower alkoxycarbonyl lower alkyl such as methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, butoxycarbonylethyl and the like or R⁷ and R⁸ taken together with the nitrogen atom to which they are attached may be joined to form a 5- or 6-membered heterocyclic ring such as pyrrolidyl, piperidyl and the like; X¹ is hydrogen, lower alkyl or lower alkoxycarbonyl; R⁹, R¹⁰, R¹¹ and R¹² are hydrogen; or R⁹ and R¹⁰ or R¹¹ and R¹² taken together with the carbon atom to which they are attached are joined to form a cycloalkyl ring of from 5 to 11 nuclear atoms either saturated or unsaturated; m' is an integer of from 0 to 2, n is an integer of 1 to 2 and the dotted line represents an optional carbon-nitrogen double bond. Especially preferred are those compounds wherein R⁷ and R⁸ taken together with the nitrogen atom to which they are attached form pyrrolidinyl and piperidinyl and n is 1. When there is a carbon-nitrogen double bond, the radical --C(═O)NR⁷ R⁸ is absent. These compounds exhibit particularly good insect repellent and residual action.

Particularly preferred compounds are: 2-azaspiro-[5.5]-undec-7-enylcarboethoxymethyl urea; 2-azaspiro-[5.5]-undec-7-enylpentamethylene urea; 2-azaspiro-[5.5]-undec-7-enyltetramethylene urea; 2-azaspiro-[5.5]-undecyltetramethylene urea; ethyl alpha(2-methyl-2-azaspiro-[5.5]-undec-7-ene)acetate; 2-azaspiro-[7.5]-tridecane; 2-azaspiro-[10.5]-hexadec-1-ene; 2-azaspiro-[5.5]-undeca-1,7-diene; 2-azaspiro-[7.5]-tridec-1-ene; 2-azaspiro-[5.5]-undec-1-ene; N-butyl-N'-3,3-diethylpentamethylene urea; 2-azaspiro-[5.5]-undec-7-enylallyl urea; ethyl- -(2-butyl-2-azaspiro-[5.5]-undec-7-ene)acetate; 2,6-dimethylpiperidyl-N-butyl urea; 2,6-dimethylpiperidyl-N-carbobutoxymethyl urea; 1-cyano-2-(2'-hydroxyethyl)-6-methyl-2-azaspiro-[5.5]-undec-8-ene and 3-azaspiro-[5.5]-undecyltetramethylene urea.

The products of this invention are prepared in a variety of ways depending upon the size of the ring or the substituent desired. Those compounds having the following formula: ##STR5## wherein R¹, R², m, n and n' are as defined above and are prepared by treating a compound of the formula: ##STR6## wherein R¹, R², X' and n' are as defined above with an alkali metal hydride such as lithium aluminum hydride and the like. Any solvent which is inert or substantially inert to the reactants may be employed such as ethers including diethylether, tetrahydrofuran and the like. The reaction may be conducted at a temperature in the range of from about 0° to about 100° C. for a period of time of from about 15 minutes to about 5 hours; however, the reaction is generally initiated at room temperature and then brought to the reflux temperature of the particular solvent employed.

The preparation of those products of this invention having an R³ substituent is illustrated by the following diagram: ##STR7##

The reaction with an isocyanate (R⁵ H═C═O) is generally conducted at a temperature in the range of from about 0° to about 50° C. in a suitably inert solvent such as benzene and the like.

The reaction with the carbamoyl halide or thiocarbamoyl halide ##STR8## wherein R⁴, R⁵ and Y are as defined above, is generally conducted at a temperature in the range of from about 0° C. to about room temperature in a suitably inert solvent such as benzene and the like.

The hydrogenation of products A and E with Raney nickel is carried out in a hydrogenator at about 40 to 50 psi of hydrogen using a suitable solvent such as methanol, ethanol and the like.

The products identified as B employed in the preparation of the products identified as A also have insect repellant activity and are prepared as follows: ##STR9##

Product F is treated with p-toluenesulfonyl chloride (TSCl) at a temperature in the range of from about 0° C. to room temperature with 0° C. being the preferred temperature using pyridine as the solvent. The ethylene acetal radical is introduced in the molecule by treating the correspondingly substituted aldehyde product (G and H) with ethylene glycol containing p-toluenesulfonic acid (TSOH) as a catalyst. Solvents which may be employed include benzene, toluene and the like. The reaction is generally conducted at the reflux temperature of the particular solvent employed.

The preparation of those compounds wherein X is alkyl, alkoxycarbonylalkyl of cyano; R³ is alkyl and there is no internal ring double bond is accomplished by methods well-known to those skilled in the art and is illustrated below. ##STR10## wherein R¹, R², R³, m, n and n' are as defined above and X' is an alkyl, alkoxycarbonylalkyl or cyano.

The compounds of this invention and compositions thereof can be employed over a wide range of concentration in a variety of carriers or diluents conventionally used in the art.

The amount of such compound employed in the insect repellent compositions can vary between from about 0.1 to about 90 weight percent basis of the weight of the composition and will depend upon the intended use. Usually, the compositions contain between about 0.1 to about 10 weight percent of one or more of the compounds, hereinbefore described, and the compound is usually in intimate mixture with the carrier.

When it is desired to use the insect repellent composition directly (i.e., without further dilution), the amount of the compound used can usually vary from between about 0.1 to 5.0 weight percent. When it is desired to formulate a concentrated composition, i.e., one suitable for dilution prior to end use, the compounds will usually be present in the composition in an amount of from about 0.5 to about 90 weight percent.

The carrier employed can be any carrier conventionally used in insect repellent formulations. The carrier should also be one that will not be harmful to the environment. The carrier can be any one of a variety of organic and inorganic liquid, solid, or semi-solid carriers or carrier formulations conventionally used in insect repellent products and can be a mixture of such carriers.

Examples of organic liquid carriers include liquid aliphatic hydrocarbons such as pentane, hexane, heptane, nonane, decane and their analogs, as well as liquid aromatic hydrocarbons. Examples of other liquid hydrocarbons include oils produced by the distillation of coal and the distillation of various types and grades of petrochemical stocks including kerosene oils which are obtained by fractional distillation of petroleum at between 84° C. and 130° C. and which usually have a flash point between 18° C. and 32° C.

Other petroleum oils include those generally referred to in the art as agricultural spray oils which are light and medium spray oils consisting of the middle fractions in the distillation of petroleum and have a viscosity in the range of from about 40 to 85 sec. Saybolt at 4° C. and are only slightly volatile. These oils are usually highly refined and contain only minute amounts of unsaturated compounds as measured by standard sulfonation tests. The customary sulfonation range of such oils is between 90% and 94% of unsulfonatable residue. These oils are paraffin oils and can be emulsified with water and an emulsifier and diluted to lower concentrations and used as sprays. Tall oils obtained from sulfate digestion of wood pulp, like paraffin oils, also can be employed.

In addition to the above-mentioned liquid hydrocarbons, the carrier can contain conventional emulsifying agents (e.g., a non-ionic surfactant such as an ethylene oxide condensate of octyl phenol or an anionic surfactant such as an alkali metal salt of an alkylbenzenesulfonic acid). Such emulsifiers are used to permit the composition to be dispersed in and diluted with water for end use application.

When paraffin oils are employed as carriers in the insect repellent compositions of this invention, they are usually used in conjunction with an emulsifier, the mixture being diluted with water immediately prior to the end-use application. Other suitable paraffin oils, particularly those used with emulsions, are referred to in the art as heavy paraffin oils and usually have a viscosity greater than 85 sec. Saybolt at 4° C.

Other advantageous organic liquid carriers can include liquid terpene hydrocarbons and terpene alcohols such as alpha-pinene, dipentene, terpineol, and the like. Still other liquid carriers include organic solvents such as aliphatic and aromatic alcohols, esters, aldehydes, and ketones. Aliphatic monohydric alcohols include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and t-butyl alcohols. Suitable dihydrin alcohols include glycols such as ethylene and propylene glycol and the pinacols (alcohols having the empirical formula: C₆ H₁₂ (OH)₂. Suitable polyhydroxy alcohols include glycerol, arabitol, erythritol, sorbitol, and the like. Suitable cyclic alcohols include cyclopentyl and cyclohexyl alcohols.

Conventional aromatic and aliphatic esters, aldehydes and ketones can be employed and are usually used in combination with the above-mentioned alcohols. Still other liquid carriers including high-boiling petroleum products, such as mineral oil and higher alcohols, such as cetyl alcohol can also be employed. Additionally, conventional "stabilizers" or "synergizers" such as t-butyl sulfinyl dimethyl dithiocarbamate, can be employed in conjunction with, or as a component of, the carriers comprising the compositions of this invention.

Solid carriers which can be used in the compositions of this invention include finely divided organic and inorganic solid materials. Suitable finely divided solid inorganic carriers include siliceous minererals such as clay, including bentonite, attapulgite, fuller's earth, diatomaceous earth, kaolin, mica, talc, finely divided quartz, and the like, as well as synthetically prepared siliceous materials, such as silica aerogels and precipitated and fume silicas.

Examples of finely divided solid organic materials include cellulose, sawdust, synthetic organic polymers and the like.

Examples of semi-solid carriers include petroleum jelly, lanolin and the like, and mixtures of liquid and solid carriers which provide semi-solid carrier products.

The above-described compositions can be employed per se or can be diluted with suitable liquids or solids to repel common flying and crawling insect pests, such as roaches, moths, house and stable flies, termites, flour beetles, bean beetles, weevils, ticks, chinch bugs, ants, chiggers, mosquitoes and the like. The compositions, when used to contact an insect environment, effectively repel the insects. By way of example, one advantageous embodiment of a composition of this invention comprises from about 0.1 to about 90 percent, preferably 0.1 to about 10 percent by weight of an active compound falling within the scope of this invention, in intimate mixture with one or more of the above-mentioned carriers.

Insect pests can be repelled by contacting the surfaces on which the insects may alight or crawl with a liquid, solid or semi-solid composition. The contact can be accomplished directly (e.g., by atomizing the composition into the air as a liquid or as a dust so that the material will fall on the desired surface).

By way of further example, insect-infested animals, such as dogs with fleas or poultry with lice, cows with ticks may be treated with the insect repellent compositions by contacting the fur and/or feathers and the lice, fleas and ticks contained therein, thereby ending the insect infestation. Also, granaries and silos can be treated with the compositions of this invention, prior to grain storage, to prevent beetle, weevil, and other insect infestations in the grain to be subsequently stored. Food packaging elements or containers including fiber, cardboard or wooden shipping containers or storage bins, flour sacks, and the like, can be treated with the compositions of this invention to prevent insect infestation.

EXAMPLE 1 2-Azaspiro-[5,5]-undec-1-ene

Step A-1-(2-Cyanoethyl)-1-formylcyclohexane

To a stirred solution of cyclohexane-carboxaldehyde (100 g.; 0.89 mole) and 50% potassium hydroxide solution (10.2 g.) is added, dropwise, acrylonitrile (50.4 g.; 0.95 mole) over the course of one hour, maintaining the reaction temperature between 50°-60° C. by occasional cooling. After all has been added, the mixture is stirred for an additional one hour until the exotherm ceases and then heated to 50°-60° C. for 30 minutes. The product is acidified with dilute hydrochloric acid, taken up into ether, washed with water, dried (MgSO₄) and distilled to afford 38% of colorless 1-(2-cyanoethyl)-1-formylcyclohexane (55.4 g.), b.p. 142°-146° C./5 mm.

Step B-1-(2-Cyanoethyl)-1-formylcyclohexane ethylene acetal

A solution containing 1-(2-cyanoethyl-1-formylcyclohexane (55.4 g.; 0.34 mole), ethylene glycol (27.9 g.; 0.45 mole) and p-toluenesulfonic acid (TSA) (100 mg.) in dry benzene (250 ml.) is heated under reflux with a Dean Stark tube for 12 hours. The solution is cooled, diluted with ether, washed with water and dried. Removal of the solvent affords 98% of 1-(2-cyanoethyl)-1-formylcyclohexane ethylene acetal (69.4 g.) as a colorless mobil liquid.

Step C-2-Azaspiro-[5,5]-undec-1-ene

To a solution of lithium aluminum hydride (12 g.; 0.32 mole) in dry tetrahydrofuran (250 ml.) is added, dropwise and while stirring, 1-(2-cyanoethyl)-1-formylcyclohexane ethylene acetal (41.8 g.; 0.20 mole) in tetrahydrofuran (50 ml.). The mixture is heated under reflux for three hours, after which time the solvent is removed under reduced pressure and ether added (500 ml.). The excess hydride is decomposed and the precipitated salts are removed by filtration. The filtrate is extracted several times with dilute hydrochloric acid and the acidic extract is allowed to stand at room temperature for one hour. The acidic extract is then made strongly alkaline with a dilute sodium hydroxide solution and extracted with ether. The ether is dried and distilled under atmospheric pressure and the residual liquid distilled to afford 53% of 2-azaspiro-[5,5]-undec-1-ene (16 g.) as a colorless mobil liquid, b.p. 65°-67° C./0.70 mm.

EXAMPLE 2 2-Azaspiro-[5,4]-dec-1-ene

Step A-1-Formyl-1-hydroxymethylcyclohexane

Methanol is added to a suspension of 37% formaldehyde solution (69 ml.) and cyclohexanecarboxaldehyde (100 g.; 0.89 mole) to afford a homogeneous solution. The mixture is cooled to 0° C. and a sodium hydroxide solution (1N; 67 ml.) is added with stirring over the course of 15 minutes. The mixture is allowed to warm to room temperature and is stirred at 25° C. overnight. The solution is then concentrated, diluted with water and extracted with ether. The ether extract is dried, evaporated in vacuo and the residual colorless liquid is distilled to afford 51% of 1-formyl-1-hydroxymethylcyclohexane (65 g.) , b.p. 120°-125° C./0.90 mm.

Step B-1-Formyl-1-hydroxymethylcyclohexane cyclic ethylene acetal

A solution containing 1-formyl-1-hydroxymethylcyclohexane (65 g.; 0.46 mole) and ethylene glycol (34.1 g.; 0.55 mole) in benzene (350 ml.) containing p-toluenesulfonic acid (100 mg.) is heated under reflux with continuous separation of water for three hours and then cooled. The benzene solution is washed with water, dried over magnesium sulfate and concentrated to afford 90% of 1-formyl-1-hydroxymethylcyclohexane cylic ethylene acetal (77 g.) as a colorless liquid.

Step C-1-Formyl-1-p-toluenesulfonyloxymethylcyclohexane cyclic ethylene acetal

A solution containing 1-formyl-1-hydroxymethylcyclohexane cyclic ethylene acetal (77 g.; 0.41 mole) in anhydrous pyridine (300 ml.) is cooled to 0° C. and p-toluenesulfonyl chloride (95.5 g.; 0.50 mole) is added in portions with stirring over 10 minutes. The mixture is then stored at 0° C. for two days, followed by dilution with water. The separated oil is extracted with ether, washed with water, dried and concentrated to afford 93% of 1-formyl-1-p-toluenesulfonyloxymethylcyclohexane cyclic ethylene acetal (130 g.) as a colorless oil.

Step D-1-Cyanomethyl-1-formylcyclohexane cyclic ethylene acetal

A solution of 1-formyl-1-p-toluenesulfonyloxymethylcyclohexane cyclic ethylene acetal (130 g.; 0.38 mole) in dimethyl sulfoxide (200 ml.) is added dropwise to a suspension of sodium cyanide (20.6 g.; 0.42 mole) in dimethyl sulfoxide (300 ml.) with stirring under nitrogen at 90°-95° C. over a period of 15 minutes. After the addition is complete, the mixture is maintained at 90° C. overnight. The dark solution is cooled, diluted with an equal volume of ice water and extracted with ether. The ether extract is washed with water, dried and concentrated to afford 60.0 g. (81% yield) of 1-cyanomethyl-1-formylcyclohexane cyclic ethylene acetal (60 g.) as a dark oil.

Step E-2-Azaspiro-[5,4]-dec-1-ene

A solution containing 1-cyanomethyl-1-formylcyclohexane cyclic ethylene acetal (60 g.; 0.31 mole) in dry tetrahydrofuran (50 ml.) is added dropwise over 30 minutes to a suspension of lithium aluminum hydride (13.3 g.; 0.35 mole) in tetrahydrofuran (200 ml.) with stirring. After the addition is complete, the mixture is heated under reflux for one hour, cooled and decomposed with aqueous sodium hydroxide solution after replacing the tetrahydrofuran with ether. The resulting ether solution is extracted with a hydrochloric acid solution (2N). The aqueous extract is washed once with ether and allowed to stand at room temperature for one hour. The aqueous solution is made strongly basic and extracted with ether. The ether extract is dried and distilled to afford B 14.5 g. (34% yield) of 2-azaspiro-[5,4]-dec-1-ene (14.5 g.) as a colorless mobile liquid, b.p. 45°-47° C./4.5 mm.

The following equation taken together with Table I illustrates the preparation of other compounds by substantially the procedure of Example 1. ##STR11##

                  TABLE I                                                          ______________________________________                                         Ex.                                      Cata-                                 No.  R.sup.1    R.sup.2        n   X'    lyst                                  ______________________________________                                         3    (CH.sub.2).sub.7      2     --    a                                       4    CH.sub.2 CH.sub.2 CHCHCH.sub.2                                                                       2     --    b                                                                  2     --    b                                       6    CH(CH.sub.3)CH.sub.2 CHCHCH.sub.2                                                                    2     --    a                                       7    (CH.sub.2).sub.6      2     --    b                                       8    (CH.sub.2).sub.10     2     --    a                                       9    (CH.sub.2).sub.5      2     4-CH.sub. 3                                                                          b                                       10    CH.sub.2 CH.sub.2 C(CH.sub.3)C(CH.sub.3)CH.sub.2                                                    2     --    b                                       11                                                                                   ##STR12##                                                                  12 (CH.sub.2).sub.3 CH(OC.sub.2 H.sub.5)CH.sub.2                                                        2     --    b                                       13   CH.sub.2 CH.sub.2 CH.sub.2 OCH.sub.2                                                                  2    --    a                                       14   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                               2   --    b                                     15   CH.sub.3   CH(C.sub.2 H.sub.5)(CH.sub.3)                                                                 2   --    b                                     16   CH.sub.3   CH.sub.2 CH.sub.2 CH.sub.3                                                                    2   --    b                                     17   CH.sub.3   (CH.sub.2).sub.8 CH.sub.3                                                                     2   --    b                                     18   CH.sub.3   φ          2   --    b                                       19 H                                                                                          ##STR13##     2   --    b                                     ______________________________________                                         Physical                                                                       Characteristics                                                                         Picrate                                                                              Elemental Analysis                                              Ex.  B.P./°C./                                                                         M.P./   Calc.      Found                                        No.  mm        °C.                                                                             C    H    N    C    H    N                              ______________________________________                                         3    103-105/2 186-    52.93                                                                               5.92 13.72                                                                               52.81                                                                               6.06 13.8                                          189                                                             4    85/4.5    154-    50.79                                                                               4.79 14.81                                                                               50.59                                                                               4.82 14.8                                          155.5                                                           5    75-80/.85 140-    52.31                                                                               4.65 14.35                                                                               52.03                                                                               4.63 14.7                                          144                                                             6    74-75/.20 183-    52.04                                                                               5.14 14.28                                                                               51.78                                                                               5.11 14.2                                          186                                                             7    70-72/.30 177-    51.77                                                                               5.62 14.21                                                                               51.82                                                                               5.82 14.5                                          178                                                             8    127-130/.10                                                                              162-    55.99                                                                               6.71 12.44                                                                               56.30                                                                               6.96 12.7                                          164.5                                                           9    60/.05    157-    51.77                                                                               5.62 14.21                                                                               51.91                                                                               5.86 14.6                                          158.5                                                           10   75-77/.25 135-    53.20                                                                               5.46 13.79                                                                               53.13                                                                               5.38 13.6                                          137                                                             11   130-140/.30                                                                              --      --   --   --   --   --   --                             12   130-140/.55                                                                              --      --   --   --   --   --   --                             13   85/.25    128-    47.12                                                                               4.75 14.66                                                                               47.49                                                                               4.80 15.0                                          129.5                                                           14   40-41/.35 180-    48.91                                                                               5.47 15.2 49.30                                                                               5.68 15.38                                         183                                                             15   45-47/.15 115-    50.25                                                                               5.80 14.65                                                                               50.17                                                                               6.02 14.64                                         117                                                             16   35-37/.15 110-    48.91                                                                               5.47 15.21                                                                               48.73                                                                               5.53 15.52                                         112                                                             17   105-108/.20                                                                              75-     55.74                                                                               7.13 12.38                                                                               54.59                                                                               7.13 12.58                                         79                                                              18   84-87/.10 147-    53.73                                                                               4.51 13.93                                                                               53.81                                                                               4.56 13.83                                         149.5                                                           19   72-74/.20 --      --   --   --   --   --   --                             ______________________________________                                    

EXAMPLE 20 2-Azaspiro-[5.5]-undecane

A solution of 2-azaspiro-[5.5]-undec-1-ene (15 g.; 0.10 mole) and one teaspoon (3 g.) of W2 Raney nickel catalyst in absolute ethanol (300 ml.) is hydrogenated at an initial pressure of B 40 psi until hydrogen uptake ceases (2 hours). The mixture is filtered through celite and the filtrate concentrated under reduced pressure. Distillation of the residual liquid yields 88% of 2-azaspiro-[5.5]-undecane (13.5 g.), b.p. 55°-57° C./0.10 mm.

By following substantially the procedure of Example 20 and by substituting for the 2-azaspiro-[5.5]-undec-1-ene recited therein 2-azaspiro[7.5]tridec-1-ene; 3,3-diethyl-3,4,5,6-tetrahydropyridine and 2-azaspiro-[5.5]undeca-1,7-diene there is obtained (Example 20A) 2-azaspiro-[7.5]tridecane, b.p. 85°-87° C./0.1 mm., (Example 20B) 3,3-diethylpiperidine, b.p. 39°-40° C./0.35 mm and (Example 20C) 2-azaspiro[5.5]-undec-7-ene, b.p. 74-75 C./0.8 mm, respectively.

EXAMPLE 21 Ethylα(2-methyl-2-azaspiro-[5.5]-undec-7-ene)acetate

Step A-2-Methyl-2-azoniaspiro-[5.5]-undeca-1,7-diene iodide

A solution of 2-azaspiro-[5.5]-undeca-1,7-diene (14.9 g.; 0.10 mole) is dissolved in dry benzene (150 ml.) and methyl iodide (21.3 g.; 0.15 mole) is added. The mixture becomes warm and a solid separates. The precipitate is filtered, washed with ether and air-dried to afford 27.0 g. (93% yield) of 2-methyl-2-azoniaspiro-[5.5]-undeca-1,7-diene iodide, m.p. 193°-194° C.

Step B-Ethylα(2-methyl-2-azaspiro-[5.5]-undec-7-ene)acetate

A solution of sodium methoxide in absolute ethanol (100 ml.; 0.035 mole) is treated with ethyl malonate (DEM) (5.6) g.; 0.035 mole). The ethanol is removed under reduced pressure and the resulting sodiomalonic ester is dissolved in dry dimethyl sulfoxide (50 ml.). 2-Methyl-2-azoniaspiro-[5.5]-undeca-1,7-diene iodide (8.73 g.; 0.03 mole) is added in one portion and the mixture is stirred and heated at 90°-120° C. for two hours, cooled, diluted with water and the separated oil is extracted with ether. The ether extract is washed with water, dried and concentrated. Distillation of the residual liquid yields 4.8 g. (50% yield) of ethyl α(2-methyl-2-azaspiro-[5.5]-undec-7-ene)acetate, b.p. 108° C./0.40 mm.

By following substantially the procedure of Example 21 and by substituting the appropriate amine and iodide for those recited therein, the following amino esters are obtained: ##STR14##

                                      TABLE II                                     __________________________________________________________________________                                       Analysis                                     Ex.                  B.P.   Picrate                                                                              Calc.    Found                               No.                                                                               R.sup.1                                                                              R.sup.2                                                                               R.sup.3                                                                              (°C./mm.)                                                                     mp °C.                                                                       C   H  N  C  H  N                             __________________________________________________________________________     22 --C.sub.2 H.sub.5                                                                    --C.sub.2 H.sub.5                                                                     CH.sub.3 --                                                                         90-93/.35                                                                             127-128                                                                             51.06                                                                              6.43                                                                              11.91                                                                             51.24                                                                             6.62                                                                              12.26                         23 --CH.sub.2 CH.sub.2 CH═CHCH.sub.2 --                                                    C.sub.2 H.sub.5 --                                                                  114-115/0.15                                                                          139-141                                                                             53.43                                                                              6.12                                                                              11.33                                                                             53.63                                                                             6.38                                                                              11.54                         24 --CH.sub.2 CH.sub.2 CH═CHCH.sub.2 --                                                    C.sub.3 H.sub.7 --                                                                  118-120/0.15                                                                          164-167                                                                             54.35                                                                              6.34                                                                              11.02                                                                             53.97                                                                             6.32                                                                              11.27                         25 --CH.sub.2 CH.sub.2 CH═CHCH.sub.2 --                                                    C.sub.4 H.sub.9 --                                                                  126-0.15                                                                              133-135                                                                             55.163                                                                             6.56                                                                              10.72                                                                             55.25                                                                             6.74                                                                              11.26                         26 --CH.sub.2 CH.sub.2 CH═CHCH.sub.2 --                                                    C.sub.5 H.sub.11 --                                                                 132-134/0.15                                                                          --   --  -- -- -- -- --                            27 --CH.sub.2 CH.sub.2 CH═CHCH.sub.2 --                                                    C.sub. 6 H.sub.13 --                                                                145-147/0.15                                                                          --   --  -- -- -- -- --                            28 --CH.sub.2 CH.sub.2 CH═CHCH.sub.2 --                                                    C.sub.7 H.sub.15 --                                                                 152-154/0.15                                                                          --   --  -- -- -- -- --                            29 --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                           CH.sub.3 --                                                                         108-110/0.15                                                                          --   --  -- -- -- -- --                            30 --C.sub.2 H.sub.5                                                                    --C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5 --                                                                  75-77/0.07                                                                            --   --  -- -- -- -- --                            31 --C.sub.2 H.sub.5                                                                    --C.sub.2 H.sub.5                                                                     C.sub.3 H.sub.7                                                                     101-105/0.45                                                                          --   --  -- -- -- -- --                            32 --C.sub.2 H.sub.5                                                                    --C.sub.2 H.sub.5                                                                     C.sub.4 H.sub.9 --                                                                  110/0.25                                                                              --   --  -- -- -- -- --                            __________________________________________________________________________

EXAMPLE 33 Alternative Procedure for Preparing 2-Azaspiro-[5.5]-undec-7-ene ##STR15##

A solution containing 1-formyl-1-cyanoethylcyclohex-3-ene (100 g.; 0.61 mole) and dry Raney nickel (10 g.) in absolute methanol (500 ml.) is hydrogenated in a Parr apparatus until hydrogen uptake ceases (3 hours). The solution is decanted from the catalyst and concentrated under reduced pressure. Distillation of the residual liquid affords 50 g. (54% yield) of 2-azaspiro-[5.5]-undec-7-ene, b.p. 74°-75° C./0.80 mm.

EXAMPLE 34 Alternative Procedure for Preparing Ethyl α-[2-methyl-2-azaspiro-[5.5]-undec-7-ene]acetate

To a solution containing ethyl bromoacetate (10 g.; 0.06 mole) in dimethyl formamide (100 ml.) is added zinc-copper couple (4.3 g.). Heating and stirring are initiated and 2-methyl-2-azoniaspiro-[5.5]-undeca-1,7-diene (8.73 g.; 0.03) mole is added in one portion. The temperature of the resulting mixture is maintained at 100° C. for 5 hours and cooled to room temperature. The solution is diluted with an equal volume of water and treated with excess concentrated ammonium hydroxide. Ether extraction, followed by drying over magnesium sulfate and subsequent distillation affords 7.0 g. (73% yield) of ethylα-[2-methyl-2-azaspiro-[5.5]-undec-7-ene]acetate, b.p. 108° C./0.40 mm.

EXAMPLE 35 2-Azaspiro-[5.5]-undecyltetramethyleneurea

A solution containing triethylamine (24.2 g.; 0.24 mole) and pyrrolidine carbamoyl chloride (32.7 g.; 0.24 mole) in benzene (200 ml.) is treated dropwise, under ice cooling, with 2-azaspiro-[5.5]-undecane (36.72 g.; 0.24 mole). After the addition is complete, the mixture is allowed to stir at room temperature for 2 hours. The precipitated triethylamine hydrochloride is collected by filtration and the filtrate is concentrated and the residual viscous oil is distilled to afford 53 g. (88% yield) of 2-azaspiro-[5.5]-undecyltetramethylene urea, b.p. 132°-135° C./0.30 mm.

EXAMPLE 36 2-Azaspiro-[5.5]-undec-7-enylpentamethylene urea

A solution containing triethylamine (101 g.; 1 mole) and piperidylcarbamoyl chloride (148 g.; 1 mol.) in toluene (1.0 l.) is treated dropwise under ice cooling with 2-azaspiro-[5.5]-undec-7-ene (151 g.; 1 mole). After the addition is complete, the mixture is allowed to stir at room temperature for 2 hours. The precipitated triethylamine hydrochloride is collected by filtration and the filtrate is concentrated and the residual oil is distilled to afford 218.5 g. (83% yield) of 2-azaspiro-[5.5]-undec-7-enylpentamethylene urea, b.p. 150°-155° C./0.55 mm. (m.p. 37°-39° C.)

EXAMPLE 37 2-Azaspiro-[5.5]-undec-7-enyl carboethoxymethyl urea

A solution containing 2-azaspiro-[5.5]-undec-7-ene (151 g.; 1 mole) in toluene (1.0 l.) is treated dropwise, under ice cooling, with ethyl isocyanatoacetate (129 g.; 1 mole). After the addition is complete, the mixture is kept at room temperature for 2 hours. The solvent is removed and the residual liquid distilled to afford 237 g. (85% yield) of 2-azaspiro-[5.5]-undec-7-enyl carboethoxymethyl urea, b.p. 188°-190° C./0.80 mm.

By following substantially the procedure of Example 37 and by substituting for the ethyl isocyanatoacetate an equivalent equimolar quantity of diethyl isocyanatophosphate, allyl isocyanate, propyl isocyanate and butyl isocyanate, there is obtained, respectively, 1-(1,0-diethylaminocarbonylphosphoramidato)-3-(2'-azaspiro-[5.5]-undec-7'ene)urea; 2-azaspiro-[5.5]-undec-7-enylallyl urea; 2-azaspiro-[5.5]-undec-7-enylpropyl urea and 2-azaspiro-[5.5]-undec-7-enylbutyl urea, m.p. 46°-49° C.

EXAMPLE 38 2-Azaspiro-[5.5]-undec-7-enetetramethylene urea

Step A-2-Azaspiro-[5.5]-undec-7-ene-carbamoyl chloride

A solution of 2-azaspiro-[5.5]-undec-7-ene (13 g.; 0.086 mole) in benzene (25 ml.) is added dropwise, under ice cooling, to a solution of phosgene (9 g.; 0.09 mole) in benzene (100 ml.). The solution is stirred at room temperature for 1 hour and concentrated under reduced pressure. Distillation of the residual colorless liquid affords 7.5 g. (41% yield) of 2-azaspiro-[5.5]-undec-7-enecarbamoyl chloride, b.p. 110°-113° C./0.50 mm.

Step B-2-Azaspiro-[5.5]-undec-7-ene tetramethylene urea

A solution containing 2-azaspiro-[5.5]-undec-7-enecarbamoyl chloride (7.5 g.; 0.035 mole) and triethylamine (3.54 g.; 0.035 mole) in benzene (50 ml.) is treated with pyrrolidine (2.49 g.; 0.035 mole) at room temperature. After 30 minutes, the triethylamine hydrochloride is collected by filtration and the filtrate is distilled to afford 7.8 g. (90% yield) of 2-azaspiro-[5.5]-undec-7-ene tetramethylene urea, b.p. 135°-138° C./0.30 mm.

By following substantially the procedure of Example 37 and by substituting for the 2-azaspiro-[5.5]-undec-7-ene recited therein an equimolar quantity of Compound A and by substituting for the ethyl isocyanato-acetate recited therein an equimolar quantity of Compound B, the following products are obtained:

    __________________________________________________________________________     Ex. No.                                                                             Compound A  Compound B   Product                                          __________________________________________________________________________     39   3,3-Diethylpiperidine                                                                      Methyl isocyanate                                                                           N--methyl-N'--3,3-diethylpenta-                                                methylene urea, m.p. 81°-83°                                     C.                                               40   3,3-Diethylpiperidine                                                                      Butyl isocyanate                                                                            N--Butyl-N'--3,3-diethylpenta-                                                 methylene urea                                   41   Tetrahydropyridine                                                                         Methyl isocyanate                                                                           N--Methyl-N'--tetrahydropyridyl                                                urea, b.p. 130°-135° C./2.5                                      mm.                                              42   Tetrahydropyridine                                                                         Ethyl isocyanate                                                                            N--Ethyl-N'--tetrahydropyridyl                                                 urea, b.p. 135°-138° C./1.5                                      mm.                                              43   Tetrahydropyridine                                                                         Propyl isocyanate                                                                           N--Propyl-N'--tetrahydropyridyl                                                urea, b.p. 125° C./0.5 mm.                44   Tetrahydropyridine                                                                         Butyl isocyanate                                                                            N--Butyl-N'--tetrahydropyridyl                                                 urea, b.p. 138° C./0.75 mm.               45   Tetrahydropyridine                                                                         tert-Butyl isocyanate                                                                       N--tert-Butyl-N'--tetrahydro-                                                  pyridyl urea, m.p. 130-4° C.              46   2-Methylpiperidine                                                                         Methyl isocyanate                                                                           N--Methyl-N'--2-methylpiperidyl                                                urea, b.p. 127°-130° C./0.5                                      mm.                                              47   2-Methylpiperidine                                                                         Propyl isocyanate                                                                           N--Propyl-N'--2-methylpiperidyl                                                urea, b.p. 120° C./0.5 mm.                48   2-methylpiperidine                                                                         Butyl isocyanate                                                                            N--Butyl-N'--2-methylpiperidyl                                                 urea, b.p. 140°-142° C./0.5                                      mm.                                              49   2-Azaspiro-[5.5]-undec-                                                                    Allyl isocyanate                                                                            2-Azaspiro-[5.5]-undec-7-                             7-ene                    enylallyl urea, b.p. 173°-                                              175° C./1.0 mm.                           50   2-Methylpiperidine                                                                         tert-Butyl isocyanate                                                                       2-Methylpiperidyl-N'--tert-                                                    butyl urea, m.p. 125°-127°                                       C.                                               51   2-Methylpiperidine                                                                         Allyl isocyanate                                                                            2-Methylpiperidyl-N'--allyl urea,                                              b.p. 140°-142° C./0.75 mm.         52   2-Methylpiperidine                                                                         Ethyl isocyanatoacetate                                                                     1-(2-Methylpiperidyl)-3-carbo-                                                 ethoxymethyl urea, b.p. 155°-                                           160° C./0.5 mm.                           53   2,6-Dimethylpiperidine                                                                     Ethyl isocyanate                                                                            2,6-Dimethylpiperidyl-N--ethyl-                                                urea, m.p. 94°-95° C.              54   2,6-Dimethylpiperidine                                                                     n-Propyl isocyanate                                                                         2,6-Dimethylpiperidyl-N--propyl                                                urea, m.p. 77°-79° C.              55   2,6-Dimethylpiperidine                                                                     n-Butyl isocyanate                                                                          2,6-Dimethylpiperidyl-N--                                                      butyl urea, (oil)                                56   2,6-Dimethylpiperidine                                                                     Ethyl isocyanatoacetate                                                                     2',6'-Dimethylpiperidyl-                                                       carboethoxymethyl urea, (oil)                    57   2,6-Dimethylpiperidine                                                                     n-Butyl isocyanatoacetate                                                                   2,6-Dimethylpiperidyl-N--                                                      carbobutoxymethyl urea, (oil)                    58   2-Ethylpiperidine                                                                          Methyl isocyanate                                                                           2-Ethylpiperidyl-N'--methyl                                                    urea, b.p. 155° C./3 mm.                  59   2-Ethylpiperidine                                                                          Ethyl isocyanate                                                                            2-Ethylpiperidyl-N'--                                                          ethyl urea, b.p. 153°-155°                                       C./3 mm.                                         60   2-Ethylpiperidine                                                                          n-Propyl isocyanate                                                                         2-Ethylpiperidyl-N'--propyl                                                    urea, b.p. 150° C./1.75 mm.               61   2-Ethylpiperidine                                                                          n-Butyl isocyanate                                                                          2-Ethylpiperidyl-N'--butyl                                                     urea, b.p. 150°-156° C./1.5                                      mm.                                              62   2-Ethylpiperidine                                                                          tert-Butyl isocyanate                                                                       2-Ethylpiperidyl-N'--tert-butyl                                                urea, m.p. 113°-114° C.            63   2-Ethylpiperidine                                                                          Allyl isocyanate                                                                            2-Ethylpiperidyl-N'--allyl urea,                                               b.p. 155°-157° C./2 mm.            64   2-Ethylpiperidine                                                                          Ethyl isocyanatoacetate                                                                     1-(2'-Ethylpiperidyl-3-carbo-                                                  ethoxymethyl urea, b.p. 175°-                                           180° C./1.75 mm.                          65   4-Ethoxycarbonyl-                                                                          Methyl isocyanate                                                                           4'-Carboethoxypiperidyl-N'--                          piperidine               methyl urea, b.p. 175°-180°                                      C./2 mm.                                         66   4-Ethoxycarbonyl-                                                                          Ethyl isocyanate                                                                            4'-Carboethoxypiperidyl-N'--                          piperidine               ethyl urea, b.p. 173°-180°                                       C./1 mm.                                         67   4-Benzylpiperidine                                                                         Methyl isocyanate                                                                           4-Benzylpiperidyl-N'--methyl urea,                                             (oil)                                            68   4-Benzylpiperidine                                                                         Ethyl isocyanate                                                                            4'-Benzylpiperidyl-N'--ethyl urea,                                             (oil)                                            69   4-Benzylpiperdine                                                                          n-Propyl isocyanate                                                                         4'-Benzylpiperidyl-N'--propyl                                                  urea, oil                                        70   4-Benzylpiperidine                                                                         n-Butyl isocyanate                                                                          4'-Benzylpiperidyl-N'--butyl                                                   urea, oil                                        71   4-Benzylpiperidine                                                                         Ethyl isocyanatoacetate                                                                     4'-Benzylpiperidyl-N--carboethoxy-                                             methyl urea, m.p. 110°-112°                                      C.                                               72   3-Azaspiro-[5,5]-un-                                                                       Pyrollidylcarbamoyl                                                                         3-azaspiro-[5.5] -undecyl-tetra-                      decane      chloride     methylene urea, b.p. 160°-164°                                    C./                                                                           3 mm.                                            73   3-Azaspiro-[5,5]-un-                                                                       Ethyl isocyanate                                                                            3-azaspiro-[5.5]-undecyl-allyl urea,                  decane                   m.p. 64°-67° C.                    74   3-Azaspiro-[5,5]-un-                                                                       Ethyl isocyanatoacetate                                                                     3-azaspiro-[5.5]-undecyl-carboethoxy                  decane                   urea, m.p. 89°-92° C.              75   2-Azaspiro-[5,5]-undec-                                                                    Cyclohexyl isocyanate                                                                       2-Azaspiro-[5.5]-undec-7-enyl urea,                   7-ene                    m.p. 103°-106° C.                  76   2-Azaspiro-[5,5]-undec-                                                                    Homopiperdylcarbamoyl-                                                                      2-Azaspiro-[5.5]-undec-7-enyl-hexa-                   7-ene       chloride     methylene urea, b.p. 159°-162°                                    C./                                                                           0.5 mm.                                          77   2-azaspiro-[5.5]-undec-                                                                    diethylamine 2-azaspiro [5.5]-undec-7-                             7-enyl carbamoyl         N',N'--diethyl urea,                                  chloride                 b.p. 112° C./0.15 mm                      78   2-azaspiro-[5.5]-undec-                                                                    methylaminoacetaldehyde                                                                     2-azaspiro-[5.5]-undec-7-                             7-enyl carbamoyl                                                                           dimethyl acetal                                                                             enyl-N'--methyl-N'--                                  chloride                 dimethoxyethyl urea,                                                           b.p. 160° C./0.02 m                       79   2-azaspiro-[5.5]-undec-                                                                    bis-(2-methylallyl)-                                                                        2-azaspiro-[5.5]-undec-7-                             7-enyl carbamoyl                                                                           amine        enyl-N',N'--2-methylallyl                             chloride                 urea, b.p. 134° C./0.00 mm                80   2-azaspiro-[5.5]-undec-                                                                    allylcyclohexylamine                                                                        2-azaspiro-[5.5]-undec-7-                             7-enyl carbamoyl         enyl-N'--allyl-N'--cyclohexyl                         chloride                 urea b.p. 70° C./0.02 m                   81   2-azaspiro-[5.5]-undec-                                                                    proline methyl ester                                                                        2-azaspiro-[5.5]-undec-7-                             7-enyl carbamoyl         enyl 2'-carbomethoxy-                                 chloride                 pynolidinyl urea, b.p.                                                         180° C./0.15 mm                           82   2-azaspiro-[5.5]-undec-                                                                    thiazolidine 2-azaspiro-[5.5]-undec-7-                             7-enyl carbamoyl         enyl-thiazolidinyl urea                               chloride                                                                  83   2-azaspiro-[5.5]-undec-                                                                    azetidine    2-azaspiro-[5.5]-undec-7-                             7-enyl carbamoyl         enyl trimethylene urea,                               chloride                 b.p. 150° C./0.15 mm                      84   2-azaspiro-[5.5]-undec-                                                                    2,5-dimethylpynolidine                                                                      2-azaspiro-[5.5]-undec-7-                             7-enyl carbamoyl         enyl 2',5'-dimethyl-                                  chloride                 pyrrolidinyl urea.                               85   2-azaspiro-[5.5]-undec-                                                                    4-carboethoxypiperidine                                                                     2-azaspiro-[5.5]-undec-7-                             7-enyl carbamoyl         enyl-4'-carboethoxy-                                  chloride                 piperidyl urea.                                  86   2-azaspiro-[5.5]-undec-                                                                    1,4-dioxa-8-azaspiro-                                                                       2-azaspiro-[5.5]-undec-7-                             7-enyl carbamoyl                                                                           [4.5]decane  enyl-1',4'-dioxa-8'-                                  chloride                 azaspiro[4.5]decyl urea.                         87   2-azaspiro-[5.5]-undec-                                                                    o-tolyl isocyanate                                                                          2-azaspiro-[5.5]-undec-7-                             7-ene                    enyl 3'-methylphenol urea.                       88   2-azaspiro-[5.5]-undec-                                                                    3,4-dimethylphenyl                                                                          2-azaspiro-[5.5]-undec-7-                             7-ene       isocyanate   enyl-3',4'-dimethylphenyl                                                      urea.                                            89   2-azaspiro-[5.5]-undec-                                                                    p-methoxyphenyl                                                                             2-azaspiro-[5.5]-undec-7-                             7-ene       isocyanate   enyl 4'-methoxyphenyl                                                          isocyanate                                       90   2-azaspiro-[5.5]-undec-                                                                    2-ethylphenyl                                                                               2-azaspiro-[5.5]-undec-7-                             7-ene       isocyanate   enyl-2'-ethylphenyl urea.                        91   2-azaspiro-[5.5]-undec-                                                                    3-chlorophenyl                                                                              2-azaspiro-[5.5]-undec-7-                             7-ene       isocyanate   enyl-3'-chlorophenyl urea.                       92   6-methyl-2-azaspiro-                                                                       propyl isocyanate                                                                           6-methyl-2-azaspiro[5.5]-                             [5.5]-undec-8-ene        undec-8-enyl propyl urea.                        93   6-methyl-2-azaspiro-                                                                       butyl isocyanate                                                                            6-methyl-2-azaspiro-[5.5]-                            [5.5]-undec-8-ene        undec-8-enyl butyl urea.                         94   6-methyl-2-azaspiro-                                                                       butyl isocyanatoacetate                                                                     6-methyl-2-azaspiro-[5.5]-                            [5.5]-undec-8-ene        undec-8-enyl carbobutoxy-                                                      methyl urea.                                     95   6-methyl-2-azaspiro-                                                                       pyrrolidine carbamoyl                                                                       6-methyl-2-azaspiro-[5.5]-                            [5.5]-undec-8-ene                                                                          chloride     undec-8-enyl-tetramethylene                                                    urea.                                            96   6-methyl-2-azaspiro-                                                                       ethyl isocyanatoacetate                                                                     6-methyl-2-azaspiro-[5.5]-                            [5.5]-undec-8-ene        undec-8-enyl carboethoxy-                                                      methyl urea.                                     97   2-azaspiro-[7.5]-                                                                          propyl isocyanate                                                                           2-azaspiro-[7.5]-tridecyl                             tridecane                propyl urea.                                     98   2-azaspiro-[7.5]-                                                                          pyrrolidine carbamoyl                                                                       2-azaspiro-[7.5]-tridecyl                             tridecane   chloride     tetramethylene urea.                             99   7,8-dimethyl-2-azaspiro-                                                                   butyl isocyanate                                                                            7,8-dimethyl-2-azaspiro-                              [5.5]-undec-7-ene        [5.5]-undec-7-enyl butyl                                                       urea.                                            100  7,8-dimethyl-2-azaspiro-                                                                   ethyl isocyanatoacetate                                                                     7,8-dimethyl-2-azaspiro-                              [5.5]-undec-7-ene        [5.5]-undec-7-enyl carbo-                                                      ethoxymethyl urea.                               101  7,8-dimethyl-2-azaspiro-                                                                   butyl isocyanatoacetate                                                                     7,8-dimethyl-2-azaspiro-                              [5.5]-undec-7-ene        [5.5]-undec-7-enyl carbo-                                                      butoxymethyl urea.                               102  7,8-dimethyl-2-azaspiro-                                                                   pyrrolidine carbamoyl                                                                       7,8-dimethyl-2-azaspiro-                              [5.5]-undec-7-ene                                                                          chloride     [5.5]-undec-7-enyl tetra-                                                      methylene urea.                                  103  tetrahydroquinoline                                                                        octyl isocyanate                                                                            tetrahydroquinolyl-N--                                                         octyl urea.                                      104  7,8-dimethyl-2-azaspiro-                                                                   propyl isocyanate                                                                           7,8-dimethyl-2-azaspiro-                              [5.5]-undec-7-ene        [5.5]-undec-7-enyl propyl                                                      urea.                                            __________________________________________________________________________

EXAMPLE 103 2-Hydroxyethyl-2-azaspiro-[5.5]-undec-7-ene

A mixture of 2-azaspiro-[5.5]-undec-7-ene (30.2 g.; 0.20 mole), 2-bromoethanol (25 g.; 0.20 mole) and triethylamine (20.2 g.) in toluene (250 ml.) is heated under reflux for 5 hours. The solution is cooled, filtered to removed triethylamine hydrobromide and the filtrate concentrated under reduced pressure. The residual liquid is distilled under reduced pressure to afford 28 g. (72% yield) of 2-hydroxyethyl-2-azaspiro-[5.5]-undec-7-ene, b.p. 90°-91° C./0.45 mm.

EXAMPLE 104 1-Cyano-2-(2'-hydroxyethyl)-6-methyl-2-azaspiro-[5.5]-undec-8-ene

Step A-[2-Methyl-1-formyl-1-(2'-azaspiro-4-cyclohexene]ethylene acetal

A solution of 2-methyl-1-formyl-1-(2'-cyanoethyl)-4-cyclohexene (122 g.; 0.69 moled), ethylene glycol (62 g.; 1.0 mole) and para-toluenesulfonic acid (300 m.) in benzene (500 ml.) is heated under reflux with a Dean Stark tube for 3 hours. The reaction mixture is cooled, washed several times with water, dried and concentrated to afford 152 g. (100% yield) of [2-methyl-1-formyl-1-(2'-cyanoethyl)-4-cyclohexene]ethylene acetal as a light yellow viscous liquid.

Step B-6-Methyl-2-azaspiro-[5.5]-undeca-1,8-diene

To a solution of lithium aluminum hydride (28.5 g.; 0.75 mole) in tetrahydrofuran (500 ml.) is added dropwise and while stirring [2-methyl-1-formyl-1-(2'-cyanoethyl)-4-cyclohexene]ethylene acetal (15.2 g.; 0.69 mole) and tetrahydrofuran (250 ml.). The mixture is heated under reflux for three hours, after which the solvent is removed under reduced pressure and ether (500 ml.) is added. The excess hydride is decomposed by adding successively water (28.5 ml.); a 15% sodium hydroxide solution (28.5 ml.) and water (85.5 ml.). The precipitated salts are removed by filtration and the filtrate is extracted several times with dilute hydrochloric acid. The acidic extract is stored at room temperature overnight then made strongly basic with a concentrated sodium hydroxide solution (25%) and the solution extracted with ether. The ether extracts are dried (MgSO₄) and the ether removed under atmospheric pressure and the residue distilled under vacuum to afford 52.6 g. (47% yield) of 6-methyl-2-azaspiro-[5.5]-undeca-1,8-diene, b.p. 74°-75° C./0.20 mm.

Step C-1-Cyano-2-(2'-hydroxyethyl)-6-methyl-2-azaspiro-[5.5]-undec-8-ene

A solution of 6-methyl-2-azaspiro-[5.5]-undeca-1,8-diene (21.2 g.; 0.13 mole) and 2-iodoethanol (22.3 g.; 0.13 mole) in benzene (200 ml.) is heated to reflux and allowed to cool. The benzene is removed under reduced pressure and dimethyl sulfoxide (250 ml.) and then sodium cyanide (9.8 g.; 0.2 mole) added. The mixture is stirred at 50° C. for 2 hours, cooled and diluted with water (750 ml.). The oil is extracted wit ether and the ether solution washed with water and dried over magnesium sulfate. The ether solution is filtered and the ether removed. Distillation of the residue under reduced pressure affords 22.5 g. (74% yield) of 1-cyano-2-(2'-hydroxyethyl)-6-methyl-2-azaspiro-[5.5]-undec-8-ene, b.p. 142°-145° C./0.55 mm.

The following test description and results illustrate the use of the novel compounds of this invention.

REPELLENCY SCREEN

Male albino guinea pigs (Perfection Breeders) are divided into groups of 2 each and placed into individual cages in a rodent battery equipped with an automatic watering system. Individual animal body weights ranged from 450 to 600 g. Feed and water were provided ad libitum. Guinea pigs are prepared for testing by clipping a patch of hair from the back with a size 10 clipper blade. This permits a residual amount of hair to be left on the animal.

Test compounds are formulated as 5% solutions in acetone. A 2.5 ml. volume of test solution is applied with a medicine dropper pipette to an area on the animal's back measuring approximately 7 cm. ×5 cm. This application results in a deposit rate of 3.5 mg./cm.². Two guinea pigs are treated with each compound. The test animal is anesthetized with sodium pentobarbital administered intraperitoneally at the rate of 35 mg./kg. and is placed in a cylindrical plastic cage with only the treated portion of the back exposed. The masked animal is introduced into an insect cage filled with either starved stable flies or yellow fever mosquitoes. Approximately 500-1000 insects are used as the challenge. The treated guinea pig is exposed to the test insects for a 5-10 minute period initially and at 3 hours post-treatment and then on a daily basis until the repellency activity of the compound terminates. The residual repellency activity of a compound is regarded as terminated when three or more test insects fed on the guinea pig during the exposure period. N. A. means not active at the test dose.

    ______________________________________                                                     Protection Time                                                                               Yellow fever                                        Example No.   Stable Fly   Mosquito                                            ______________________________________                                         1             4 days (D)   7 Days (D)                                          2             0.5 Hours (H)                                                                               0.5 Hours (H)                                       3             2D           8D                                                  4             3D           8D                                                  5             3H           3H                                                  6             3H           3H                                                  7             3H           3H                                                  8             4D           3H                                                  9             3H           3H                                                  10            2D           3H                                                  11            3H           1D                                                  17            1D           1D                                                  19            3H                                                               20            3H           3H                                                  20A           4D           1D                                                  20B           3H           1D                                                  21            3D           2D                                                  22            1D           2D                                                  23            2D           3H                                                  24            3D           3H                                                  25            4D           3H                                                  26            1D           3H                                                  27            3H           3H                                                  28            3H           3H                                                  29            2D           1D                                                  30            2D           2D                                                  31            3D           1D                                                  32            2D           2D                                                  35            17D          20D                                                 36            4D           4D                                                  37            7D           12D                                                 38            8D           8D                                                  39            Not Active   0.5H                                                40            3D           6D                                                  41            Not Active   3H                                                  47            0.5H         2 + D                                               48            2D           2D                                                  50            1D           0.5H                                                51            2D           0.5H                                                52            2D           3H                                                  53            0.5H         NA                                                  54            NA           0.5H                                                55            8D           8D                                                  56            2D           NA                                                  57            7D           7D                                                  58            0.5H         2D                                                  59            0.5H         2D                                                  60            3H           3D                                                  61            3H           2D                                                  62            3H           3H                                                  63            2D           3H                                                  64            2D           3H                                                  65            3H           3H                                                  66            3H           3H                                                  67            NA           0.5H                                                68            0.5H         0.5H                                                69            NA           0.5H                                                70            3H           3H                                                  71            3H           3H                                                  72            6D           7D                                                  73            NA           2D                                                  74            0.5H         NA                                                  75            0.5H         0.5H                                                76            4D           3H                                                  77            3D           3D                                                  78            3D           4D                                                  79            0.5H         0.5H                                                80            0.5H         0.5H                                                81            5D           8D                                                  82            6D           6D                                                  83            1D           1D                                                  84            1D           3D                                                  85            6D           6D                                                  86            0.5H         3H                                                  87            0.5H         0.5H                                                88            0.5H         0.5H                                                89            0.5H         0.5H                                                90            0.5H         0.5H                                                91            0.5H         0.5H                                                92            0.5H         0.5H                                                93            0.5H         0.5H                                                94            0.5H         0.5H                                                95            1D           1D                                                  96            1D           1D                                                  97            1D           3H                                                  98            3H           3H                                                  99            3H           3H                                                  100           3H           3H                                                  101           0.5          3H                                                  102           1D           1D                                                  103           3D           3D                                                  104           3D           6D                                                  ______________________________________                                     

What is claimed is:
 1. A method for repelling arthropods which comprises applying to the loci to be freed or protected from attack by arthropods an effective repellent amount of a compound selected from: ##STR16## wherein R¹ is hydrogen, lower alkyl of from 1 to 9 carbon atoms or lower alkenyl of from 2 to 5 carbon atoms; R² is lower alkyl of from 1 to 9 carbon atoms, cycloalkyl of from 4 to 6 nuclear carbon atoms or phenyl or R¹ or R², taken together with the carbon atoms to which they are attached, form a cycloalkyl or cycloalkoxy alkyl of from 5 to 11 nuclear carbon atoms; R³ is hydrogen, lower alkyl of from 1 to 5 carbon atoms, hydroxy ethyl or lower alkoxy carbonyl of from 2 to 6 carbon atoms; X is lower alkyl of from 1 to 5 carbon atoms, lower alkoxy of from 1 to 5 carbon atoms, lower alkoxycarbonyl lower alkyl or cyano; m is an integer of 0 to 2, and n and n' are integers having a value of 1 to 2, and the dotted line indicates provision for a carbon to carbon double bond with the proviso that when there is a carbon to nitrogen double bond R¹ and R², taken together with the carbon atom to which they are attached, is other than cyclopentyl.
 2. The method of claim 1 wherein the repellent comprises 2-azaspiro-[5.5]-undec-1-ene.
 3. The method of claim 1 wherein the repellent comprises 2-azaspiro-[7.5]-tridec-1-ene.
 4. The method of claim 1 wherein the repellent comprises 2-azaspiro-[5.5]-undec-1,7-diene.
 5. The method of claim 1 wherein the repellent comprises 2-azaspiro-[10.5]-hexadec-1-ene.
 6. The method of claim 1 wherein the repellent comprises 2-azaspiro-[7.5]-tridecane.
 7. The method of claim 1 wherein the repellent comprises ethyl alpha-(2-methyl-2-azaspiro-[5.5]-undec-7-ene)acetate.
 8. The method of claim 1 wherein the repellent comprises 2-hydroxyethyl-2-azaspiro-[5.5]-undec-7-ene.
 9. The method of claim 1 wherein the repellent comprises 1-cyano-2-(2'-hydroxyethyl)-6-methyl-2-azaspiro-[5.5]-undec-8-ene.
 10. An insect repellent composition which comprises from about 0.1 to about 90% of 2-azaspiro-[5.5]-undec-1-ene by weight of the composition and an inert carrier.
 11. An insect repellent composition which comprises from about 0.1 to about 90% of 2-azaspiro-[7.5]-tridec-1-ene by weight of the composition and an inert carrier.
 12. An insect repellent composition which comprises from about 0.1 to about 90% of 2-azaspiro-[5.5]-undec-1,7-diene by weight of the composition and an inert carrier.
 13. An insect repellent composition which comprises from about 0.1 to about 90% of 2-azaspiro-[10.5]-hexadec-1-ene by weight of the composition and an inert carrier.
 14. An insect repellent composition which comprises from about 0.1 to about 90% of 2-azaspiro-[7.5]-tridecane by weight of the composition and an inert carrier.
 15. An insect repellent composition which comprises from about 0.1 to about 90% of ethyl alpha-(2-methyl-2-azaspiro-[5.5]-undec-7-ene)-acetate by weight of the composition and an inert carrier.
 16. An insect repellent composition which comprises from about 0.1 to about 90% of 2-hydroxyethyl-2-azaspiro-[5.5]-undec-7-ene by weight of the composition and an inert carrier.
 17. An insect repellent composition which comprises from about 0.1 to about 90% of 1-cyano-2-(2'-hydroxyethyl)-6-methyl-2-azaspiro-[5.5]-undec-8-ene by weight of the composition and an inert carrier. 